Topics:

Viral Mouthwash Kills Cells That Lack Normal p53

Viral Mouthwash Kills Cells That Lack Normal p53

ATLANTA—Mouthwash containing a modified virus that kills cells lacking p53 (a common deletion in many cancerous and precancerous lesions) may prevent development of invasive squamous cell head and neck cancers in smokers, researchers reported at the annual meeting of the American Society of Clinical Oncology.

The ONYX-015 agent is an attenuated adenovirus that is unable to productively infect normal human cells, but can replicate in and lyse cells that do not have normal p53 function.

The viral agent is being tested in advanced solid tumors, but a poster presented by Charles W. Rudin, MD, PhD, and his colleagues at the University of Chicago suggested that it may be even more effective at preventing premalignant lesions from developing into full-fledged cancers.

One of the normal cellular responses to adenovirus infection is to turn on p53 expression, if p53 is present. Normal cells infected with ONYX-015 would thus activate p53. Cells unable to activate p53, such as precancerous cells that have lost p53 function, are unable to defuse the virus and are destroyed.

Dr. Rudin reported preliminary results of a phase I/II trial of ONYX-015 given as a mouthwash for the treatment of clinically evident oropharyngeal dysplastic lesions. The mouthwash containing ONYX-015 was administered daily for 5 days, with treatments repeated every 4 weeks. For each patient, doses were escalated from a starting dose of 108 pfu/d.

“Patients with dysplastic lesions of the oropharynx, including erythroplakia and leukoplakia, are at high risk for the development of invasive squamous cell carcinoma of the head and neck,” Dr. Rudin said. “An estimated 45% to 50% of these dysplastic lesions carry inactivating mutations of the p53 gene, and a proportion of the remaining dysplastic lesions may have functional defects in p53 response pathways.”

This trial is designed to include 20 patients. Dr. Rudin reported data on the first five. The first patient, with a history of invasive squamous cell carcinoma, had severe dysplasia. Two others had mild-to-moderate dysplasia or focal dysplasia, and two had hyperplasia.

The first patient was a 28-year-old woman with a carcinoma of the tongue that had been resected via a hemiglossectomy. She had recurrence at the surgical margin with a 1-cm plaque of leukoplakia that, on biopsy, was severely dysplastic. The lesion was p53-abnormal through the full thickness of the mucosa.

“This was a worrisome, genetically abnormal lesion in a patient who previously had cancer. This patient was at extremely high risk for cancer recurrence,” Dr. Rudin said.

The patient was treated with the ONYX-015 mouthwash daily for 5 days and was biopsied again the next week. “The surgeon [who was scheduled to re-biopsy the 1-cm plaque] called me and said, ‘I’m supposed to biopsy this lesion, but it’s gone,’” Dr. Rudin said. “We told her to biopsy the mucosa where the plaque had been, and it showed only mild dysplasia with minimal abnormal cells after only one cycle of the mouthwash.”

Complete Resolution

The patient has been treated with 11 cycles so far and has had a complete resolution of all evidence of dysplasia. There is no abnormality evident in the mucosa, and the tissue is now p53 normal by immunohistochemistry. “We think we have taken a woman who was at extremely high risk for cancer recurrence and may have significantly reduced that risk,” he said.

Dr. Rudin cautioned that whether this benefit would be sustained if treatment were halted is yet to be determined. The patient will receive one more cycle of treatment, then will be monitored for 6 months for signs of recurrence.

Dr. Rudin said that no adverse effects have been noted up to the final dose level of 1010 pfu/day in patients treated daily for 1 week per month.

Use of the ONYX-015 mouthwash will be expanded in a multi-institution trial in oral dysplasia, he said.

The most striking thing about the study is that the entire oral surface was exposed to the adenovirus, said David H. Kirn, MD, vice president for clinical research at Onyx Pharmaceuticals, which developed the mouthwash. “The normal cells were entirely unaffected, but the dysplastic lesions resolved in the two patients who were p53 abnormal,” Dr. Kirn said. “This study is the result of 20 years of basic research on what is essentially a common cold virus—adenovirus. It is a poster child for translational research.”

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.